An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

F. A J van de Loo, A. S K de Hooge, R. L. Smeets, A. C. Bakker, M. B. Bennink, O. J. Arntz, L. A B Joosten, H. M. van Beuningen, P. K. van der Kraan, A. W. Varley, W. B. van den Berg

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43 Scopus citations

Abstract

To achieve a disease-regulated transgene expression for physiologically responsive gene therapy of arthritis, a hybrid promoter was constructed. The human IL-1β enhancer region (-3690 to -2720) upstream of the human IL-6 promoter region (-163 to +12) was essential in mounting a robust response in HIG-82 synovial fibroblasts and in RAW 264,7 macrophages. A replication-deficient adenovirus was engineered with luciferase (Luc) controlled by the IL-1/IL-6 promoter (Ad5.IL-1/IL-6-Luc). LPS caused a 23- and 4.6-fold induction of Luc. activity in RAW cells infected with Ad5.IL-1/ IL-6-Luc or the conventional Ad5.CMV-Luc construct, respectively. Next, adenoviruses (106 ffu) were injected into the knees of C57BI/6 mice. An intra-articular injection of zymosan, 3 days after Ad5.IL-1/IL-6-Luc, increased Luc. activity by 39-fold but had no effect in the Ad5.CMV-Luc joints. The constitutive CMV promoter was rapidly silenced and could not be reactivated in vivo. In contrast, the IL-1/IL-6 promoter could be reactivated by Streptococcal cell wall (SCW)-induced arthritis up to 21 days after infection. Next the IL-1/IL-6 promoter was compared to the C3-Tat/HIV-LTR two-component system in wild-type, IL-6-/- and IL-1-/- gene knockout mice. Both systems responded well to LPS-, zymosan- and SCW-induced arthritis. However, the basal activity of the IL-1/IL-6 promoter was lower and IL-6 independent. This study showed that the IL-1/IL-6 promoter is feasible to achieve disease-regulated transgene expression for treatment of arthritis.

Original languageEnglish (US)
Pages (from-to)581-590
Number of pages10
JournalGene Therapy
Volume11
Issue number7
DOIs
Publication statusPublished - Apr 2004

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Keywords

  • Adenovirus
  • Arthritis
  • Gene knockout
  • Inducible promoter
  • Mice

ASJC Scopus subject areas

  • Genetics

Cite this

van de Loo, F. A. J., de Hooge, A. S. K., Smeets, R. L., Bakker, A. C., Bennink, M. B., Arntz, O. J., ... van den Berg, W. B. (2004). An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint. Gene Therapy, 11(7), 581-590. https://doi.org/10.1038/sj.gt.3302182